Document Type : Original Article


1 Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran

2 Department of Colorectal Surgery, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran


Background: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system (CNS) that prompts immediate potent treatment. Delaying treatment could leave debilitating sequelae. As erythropoietin (EPO) has shown neuroprotective effects, we studied the effects of adding EPO to intravenous methylprednisolone (IVMP) in patients with acute attacks of NMOSD.
Methods: NMOSD cases with acute attacks were included. Cases of optic neuritis (ON) and those with myelitis were separated. After randomization [with block sizes of 2 (1:1 ratio)], the patients in the intervention group received IVMP 1000 mg/day and intravenous (IV) EPO 20000 U/day for five days. IVMP 1000 mg/day and normal saline (NS) were administered in the control group. Staged eye score and motor forces were evaluated in the patients with ON and myelitis, respectively, at the time of the attack and three months later. Primary patient allocation and clinical assessments were blinded to the physicians.
Results: Mean age of participants was 53.87 ± 11.53 years. At follow-up, in the ON arm, the median improvement in staged eye score was 2 in the control and 5 in the intervention group. 
The difference was significant (P < 0.001). In the myelitis group, none of the patients in the control group had improvement in motor forces. All the patients in the intervention group showed substantial improvement with minimal or no remaining weakness. The difference was statistically significant (P = 0.029).
Conclusion: The results show the possible benefit of adding EPO to the classic IVMP in attacks of NMOSD in both visual and motor aspects.


  1. Etemadifar M, Nasr Z, Khalili B, Taherioun M, Vosoughi R. Epidemiology of neuromyelitis optica in the world: A systematic review and meta-analysis. Mult Scler Int 2015; 2015: 174720.
  2. Fazio R, Malosio ML, Lampasona V, De FD, Privitera D, Marnetto F, et al. Antiacquaporin 4 antibodies detection by different techniques in neuromyelitis optica patients. Mult Scler 2009; 15(10): 1153-63.
  3. Weinshenker BG. Plasma exchange for acute attacks of demyelinating disease: Detecting a Lazarus effect. Ther Apher 2000; 4(3): 187-9.
  4. Bonnan M, Cabre P. Plasma exchange in severe attacks of neuromyelitis optica. Mult Scler Int 2012; 2012: 787630.
  5. Yamasaki R, Matsushita T, Fukazawa T, Yokoyama K, Fujihara K, Ogino M, et al. Efficacy of intravenous methylprednisolone pulse therapy in patients with multiple sclerosis and neuromyelitis optica. Mult Scler 2016; 22(10): 1337-48.
  6. Fisher JW. Erythropoietin: Physiology and pharmacology update. Exp Biol Med (Maywood) 2003; 228(1): 1-14.
  7. Rey F, Balsari A, Giallongo T, Ottolenghi S, Di Giulio AM, Samaja M, et al. Erythropoietin as a neuroprotective molecule: An overview of its therapeutic potential in neurodegenerative diseases. ASN Neuro 2019; 11: 1759091419871420.
  8. Punnonen J, Miller JL, Collier TJ, Spencer JR. Agonists of the tissue-protective erythropoietin receptor in the treatment of Parkinson's disease. Curr Top Med Chem 2015; 15(10): 955-69.
  9. Li YP, Yang GJ, Jin L, Yang HM, Chen J, Chai GS, et al. Erythropoietin attenuates Alzheimer-like memory impairments and pathological changes induced by amyloid beta42 in mice. Brain Res 2015; 1618: 159-67.
  10. Castaneda-Arellano R, Beas-Zarate C, Feria-Velasco AI, Bitar-Alatorre EW, Rivera-Cervantes MC. From neurogenesis to neuroprotection in the epilepsy: Signalling by erythropoietin. Front Biosci (Landmark Ed) 2014; 19(8): 1445-55.
  11. Souvenir R, Doycheva D, Zhang JH, Tang J. Erythropoietin in stroke therapy: Friend or foe. Curr Med Chem 2015; 22(10): 1205-13.
  12. Maiese K. Charting a course for erythropoietin in traumatic brain injury. J Transl Sci 2016; 2(2): 140-4.
  13. Javed S, Alam U, Malik RA. Treating diabetic neuropathy: present strategies and emerging solutions. Rev Diabet Stud 2015; 12(1-2): 63-83.
  14. Najmi VF, Najmi VF, Azimi AR, Rezaei N, Sahraian MA. Efficacy of combination therapy with erythropoietin and methylprednisolone in clinical recovery of severe relapse in multiple sclerosis. Acta Neurol Belg 2014; 114(4): 273-8.
  15. Moransard M, Bednar M, Frei K, Gassmann M, Ogunshola OO. Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms. J Neuroinflammation 2017; 14(1): 202.
  16. Gingele S, Stangel M. Emerging myelin repair agents in preclinical and early clinical development for the treatment of multiple sclerosis. Expert Opin Investig Drugs 2020; 29(6): 583-94.
  17. Mirzaie J, Raoofi A, Jamalpoor Z, Nezhadi A, Golmohammadi R. Protective impacts of erythropoietin on myelinization of oligodendrocytes and schwann cells in CNS and PNS following cuprizone-induced multiple sclerosis- histology, molecular, and functional studies. J Chem Neuroanat 2020; 104: 101750.
  18. Dasgupta S, Mazumder B, Ramani YR, Bhattacharyya SP, Das MK. Evaluation of the role of erythropoietin and methotrexate in multiple sclerosis. Indian J Pharmacol 2011; 43(5): 512-5.
  19. Diem R, Sattler MB, Merkler D, Demmer I, Maier K, Stadelmann C, et al. Combined therapy with methylprednisolone and erythropoietin in a model of multiple sclerosis. Brain 2005; 128(Pt 2): 375-85.
  20. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015; 85(2): 177-89.
  21. Schreiber K, Magyari M, Sellebjerg F, Iversen P, Garde E, Madsen CG, et al. High-dose erythropoietin in patients with progressive multiple sclerosis: A randomized, placebo-controlled, phase 2 trial. Mult Scler 2017; 23(5): 675-85.
  22. Shayegannejad V, Shahzamani S, Dehghani A, Dast BZ, Rahimi M, Mirmohammadsadeghi A. A double-blind, placebo-controlled trial of adding erythropoietin to intravenous methylprednisolone for the treatment of unilateral acute optic neuritis of unknown or demyelinative origin. Graefes Arch Clin Exp Ophthalmol 2015; 253(5): 797-801.
  23. Suhs KW, Hein K, Sattler MB, Gorlitz A, Ciupka C, Scholz K, et al. A randomized, double-blind, phase 2 study of erythropoietin in optic neuritis. Ann Neurol 2012; 72(2): 199-210.
  24. Masuda S, Okano M, Yamagishi K, Nagao M, Ueda M, Sasaki R. A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem 1994; 269(30): 19488-93.
  25. Juul SE, Yachnis AT, Rojiani AM, Christensen RD. Immunohistochemical localization of erythropoietin and its receptor in the developing human brain. Pediatr Dev Pathol 1999; 2(2): 148-58.
  26. Yang L, Yan X, Xu Z, Tan W, Chen Z, Wu B. Delayed administration of recombinant human erythropoietin reduces apoptosis and inflammation and promotes myelin repair and functional recovery following spinal cord compressive injury in rats. Restor Neurol Neurosci 2015; 34(4): 647-63.
  27. Yuan R, Wang B, Lu W, Maeda Y, Dowling P. A distinct region in erythropoietin that induces immuno/inflammatory modulation and tissue protection. Neurotherapeutics 2015; 12(4): 850-61.
  28. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 2004; 35(7): 1732-7.
  29. Genc K, Genc S, Baskin H, Semin I. Erythropoietin decreases cytotoxicity and nitric oxide formation induced by inflammatory stimuli in rat oligodendrocytes. Physiol Res 2006; 55(1): 33-8.
  30. Vittori DC, Chamorro ME, Hernandez YV, Maltaneri RE, Nesse AB. Erythropoietin and derivatives: Potential beneficial effects on the brain. J Neurochem 2021; 158(5): 1032-57.